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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Antifungal activity of LY303366, a novel echinocandin B, in experimental disseminated candidiasis in rabbits.
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Antifungal activity of LY303366, a novel echinocandin B, in experimental disseminated candidiasis in rabbits.

机译：新型棘皮菌素B LY303366在兔实验性念珠菌病中的抗真菌活性。

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摘要

The safety and antifungal activity of LY303366 (LY), a new broad-spectrum semisynthetic echinocandin, were studied against disseminated candidiasis in persistently neutropenic rabbits. In vitro time-kill assays demonstrated that LY has concentration-dependent fungicidal activity. The pharmacokinetics of LY in the plasma of nonneutropenic rabbits suggested a linear relationship between dose and area under the curve (AUC). The times spent above the MIC during the experimental dosing interval of 24 h were 4 h for LY at 0.1 mg/kg of body weight/day (LY0.1), 8 h for LY at 0.25 mg/kg/day (LY0.25), 12 h for LY at 0.5 mg/kg/day (LY0.5), and 20 h for LY at 1 mg/kg/day (LY1). Antifungal therapy was administered to infected rabbits for 10 days starting 24 h after the intravenous (i.v.) inoculation of 10(3) Candida albicans blastoconidia. Study groups consisted of untreated controls (UCs) and animals treated with amphotericin B (AmB; 1 mg/kg/day i.v.), fluconazole (FLU; 10 mg/kg/day i.v.), and LY0.1, LY0.25, LY0.5, or LY1 i.v. Rabbits treated with LY0.5, LY1, AmB, and FLU had similarly significant clearance of C. albicans from the liver, spleen, kidney, lung, vena cava, and brain in comparison to that for UCs. There was a dose-dependent clearance of C. albicans from tissues in response to LY. Among rabbits treated with LY0.1 there was a significant reduction of C. albicans only in the spleen. In animals treated with LY0.25 there was a significant reduction in all tissues but the brain. By comparison, LY0.5 and LY1 cleared all tissues, including the brain, of C. albicans. These in vivo findings were consistent with the results of in vitro time-kill assays. A dose-dependent effect of altered cell wall morphology was observed among UCs and animals treated with LY0.1, and LY0.25, with a progressive transition from hyphal structure to disrupted yeast forms. Serum creatinine levels were higher and serum potassium levels were lower in AmB-treated rabbits than in UCs and LY- and FLU-treated rabbits. LY0.5 and LY1 were well tolerated, displayed predictable pharmacokinetics in plasma, and had activities comparable to those of AmB and FLU in the treatment of disseminated candidiasis in persistently neutropenic rabbits.
机译：研究了新型广谱半合成棘皮菌素LY303366（LY）的安全性和抗真菌活性，对持续嗜中性白血球减少症兔的念珠菌病具有预防作用。体外时间杀灭试验表明，LY具有浓度依赖性的杀真菌活性。 LY在非中性粒细胞减少兔血浆中的药代动力学表明剂量与曲线下面积（AUC）之间呈线性关系。在实验剂量间隔24小时内，在MIC上方花费的时间对于LY为0.1 mg / kg体重/天（LY0.1）为4小时，LY为0.25 mg / kg /天（LY0.25）8小时），0.5 mg / kg /天（LY0.5）的LY 12小时和1 mg / kg /天（LY1）的LY 20小时。在静脉内（i.v.）接种10（3）白色念珠菌病原菌后24小时，对感染的兔子进行抗真菌治疗，持续10天。研究组由未经治疗的对照（UCs）和用两性霉素B（AmB; 1 mg / kg / day iv），氟康唑（FLU; 10 mg / kg / day iv）和LY0.1，LY0.25，LY0治疗的动物组成.5或LY1 iv与UCs相比，用LY0.5，LY1，AmB和FLU处理的兔子从肝脏，脾脏，肾脏，肺，腔静脉和大脑清除白色念珠菌的能力相似。响应于LY，白色念珠菌从组织中的剂量依赖性清除。在用LY0.1治疗的兔子中，仅在脾脏中白念珠菌显着减少。在用LY0.25治疗的动物中，除脑外所有组织均明显减少。相比之下，LY0.5和LY1清除了白色念珠菌的所有组织，包括大脑。这些体内发现与体外时间杀灭测定的结果一致。在用LY0.1和LY0.25处理的UC和动物中，观察到了改变的细胞壁形态的剂量依赖性效应，并从菌丝结构逐渐转变为破坏的酵母形式。与UCs，LY和FLU治疗的兔子相比，AmB治疗的兔子的血清肌酐水平较高，而血清钾水平较低。 LY0.5和LY1具有良好的耐受性，在血浆中显示出可预测的药代动力学，在治疗持续性中性粒细胞减少症兔的散播性念珠菌病中具有与AmB和FLU相当的活性。

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